The nucleosome is the fundamental packing unit of chromatin formed by association of DNA and histone octamer in eukaryotic chromosomes. The detailed locations of nucleosomes along genomic DNA are critical for proper gene regulation - and therefore for the health and development of humans and all other eukaryotes - yet, at present, we lack any methods for the """"""""in-silico"""""""" prediction of nucleosome positioning sequence elements in genomes. The long-term goal of this project is to develop capability to predict nucleosome-forming propensity given DNA sequences and correlate the genome-wide distribution of nucleosome-forming sequences with chromosome function. Towards this goal, we propose to achieve the following five aims progressively in the subsequent years. (1) Experimentally collect 1000 yeast nucleosome core DNA sequences, and 1000 yeast di-nucleosome DNA sequences (two neighboring nucleosomes linked by linker DNA). These yeast nucleosome DNA sequences will form a new training set as well as a validating set for nucleosome positioning prediction across the yeast genome. (2) Develop and refine statistical methods to align nucleosome DNA sequences. A novel statistical model for nucleosorne DNA sequence alignment was proposed in the preliminary study. We will refine this model by introducing a weighting scheme based on the importance of different periodic di-nucleotide signals from free energy consideration. (3) Use the alignment in (2) to train a model to predict nucleosome positioning. An inhomogeneous Markov chain model and a """"""""mixture train"""""""" model are under consideration to model the sequential dependent structure of nucleotides. (4) Generalize the model by incorporating knowledge in spacing properties of neighboring nucleosomes. The di-nucleosome sequences generated from (1) will provide distributional evidence for between-nucleosome space and dl1 greatly facilitate prediction of genome-wide nucleosome positioning. (5) Automate the developed tools and algorithms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM075313-05S1
Application #
8063238
Study Section
Special Emphasis Panel (ZGM1-CBCB-0 (BM))
Program Officer
Gaillard, Shawn R
Project Start
2010-04-30
Project End
2011-03-31
Budget Start
2010-04-30
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$103,601
Indirect Cost
Name
Northwestern University at Chicago
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Xi, Liqun; Brogaard, Kristin; Zhang, Qingyang et al. (2014) A locally convoluted cluster model for nucleosome positioning signals in chemical map. J Am Stat Assoc 109:48-62
Nalabothula, Narasimharao; Xi, Liqun; Bhattacharyya, Sucharita et al. (2013) Archaeal nucleosome positioning in vivo and in vitro is directed by primary sequence motifs. BMC Genomics 14:391
Brogaard, Kristin R; Xi, Liqun; Wang, Ji-Ping et al. (2012) A chemical approach to mapping nucleosomes at base pair resolution in yeast. Methods Enzymol 513:315-34
Brogaard, Kristin; Xi, Liqun; Wang, Ji-Ping et al. (2012) A map of nucleosome positions in yeast at base-pair resolution. Nature 486:496-501
Wang, Ji-Ping; Fondufe-Mittendorf, Yvonne; Xi, Liqun et al. (2008) Preferentially quantized linker DNA lengths in Saccharomyces cerevisiae. PLoS Comput Biol 4:e1000175
Brickner, Donna Garvey; Cajigas, Ivelisse; Fondufe-Mittendorf, Yvonne et al. (2007) H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. PLoS Biol 5:e81
Wang, Ji-Ping Z; Widom, Jonathan (2005) Improved alignment of nucleosome DNA sequences using a mixture model. Nucleic Acids Res 33:6743-55